Published Ahead of Print on October 8, 2015 as 10.1634/theoncologist.2015-0245.
Clinical Trial Results
A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas RODRIGO R. MUNHOZ,a SANDRA P. D’ANGELO,a,b MRINAL M. GOUNDER,a,b MARY L. KEOHAN,a,b PING CHI,a,b RICHARD D. CARVAJAL,c SAMUEL SINGER,a,b AIMEE M. CRAGO,a,b JONATHAN LANDA,a,b JOHN H. HEALEY,a,b LI-XUAN QIN,a,b MEERA HAMEED,a,b MARIETTA O. EZEOKE,a ARUN S. SINGH,d MARK AGULNIK,e BARTOSZ CHMIELOWSKI,d JASON J. LUKE,f BRIAN A. VAN TINE,g GARY K. SCHWARTZ,c WILLIAM D. TAP,a,b MARK A. DICKSONa,b a
Memorial Sloan Kettering Cancer Center, New York, New York, USA; bWeill Cornell Medical College, New York, New York, USA; Columbia University Medical Center, New York, New York, USA; dUniversity of California at Los Angeles, Los Angeles, California, USA; e Northwestern University, Chicago, Illinois, USA; fUniversity of Chicago, Chicago, Illinois USA; gWashington University in St. Louis, St. Louis, Missouri, USA Access the full results at: Dickson-15-245.theoncologist.com c
LESSONS LEARNED x Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients.The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib. x Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.
ABSTRACT Background. For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. Methods. Patients with high grade, extremity STS of .8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m2 gemcitabine on days 1 and 8, 75 mg/m2 docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. Results. The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had $90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. Conclusion. GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred. The Oncologist 2015;20:1–2
DISCUSSION The role of systemic therapy in the management of patients with localized STS is a topic of ongoing debate. We sought to investigate whether the addition of pazopanib to gemcitabine/ docetaxel (GDP) in the neoadjuvant setting would be safe and result in an antitumor effect in patients with localized, high grade (limited to undifferentiated pleomorphic sarcoma, high grade leiomyosarcoma, and malignant peripheral nerve sheath tumor), extremity STS of .8 cm amenable to definitive
ClinicalTrials.gov Identifier: NCT01418001 Sponsor: Memorial Sloan Kettering Cancer Center
Principal Investigator: William D. Tap IRB Approved: Yes
Correspondence: Mark A. Dickson, M.D., Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 East 66th Street, New York, New York 10065. Telephone: 646-888-4164; E-Mail: [email protected] Received June 16, 2015; accepted for publication August 19, 2015. ©AlphaMed Press; the data published online to support this summary is the property of the authors. http://dx.doi.org/10.1634/ theoncologist.2015-0245
The Oncologist 2015;20:1–2 www.TheOncologist.com
©AlphaMed Press 2015
Downloaded from http://theoncologist.alphamedpress.org/ by guest on October 28, 2015
AUTHOR SUMMARY
Published Ahead of Print on October 8, 2015 as 10.1634/theoncologist.2015-0245.
Neoadjuvant Treatment of Soft Tissue Sarcomas
2
Table 1. Efficacy and treatment summary Best response (change from baseline)
Pt
Histology
Age
Sex
No. of cycles
1
UPS
65
M
2
SD (27.4%)
2
LMS
67
M
3
SD (23.0%)
3 4
UPS UPS
72 42
M F
4 4
SD (21.7%) POD (123.2%)
5
LMS
78
M
2
SD (24.2%)
Pathologic outcomes
AE > grade 2
90% treatment effect; clear surgical margins 10% treatment effect; clear surgical margins Did not undergo surgery 70% treatment effect; clear surgical margins 10% treatment effect; involved surgical margins
Hypertension, fatigue, thrombocytopenia, hoarseness AST/ALT elevation None AST/ALT elevation, lymphopenia Anemia, lymphopenia
Abbreviations: AE, adverse events; AST/ALT, aspartate aminotransferase or alanine aminotransferase; F, female; LMS, leiomyosarcoma; M, male; POD, progression of disease; Pt, patient; SD, stable disease; UPS, undifferentiated pleomorphic sarcoma.
developed lung metastases. Treatment/outcome details are provided in Table 1. Studies investigating neo- or adjuvant systemic treatments in STS have yielded conflicting results. A meta-analysis suggested a marginal improvement in local recurrence, distant recurrence, and overall survival with adjuvant chemotherapy in patient with resectable STS; however, subsequent prospective trials have not confirmed this. In conclusion, the question of whether neoadjuvant chemotherapy can improve the outcomes of patients with localized, high-grade extremity STS remains unanswered. The addition of pazopanib to gemcitabine and docetaxel resulted in significant toxicity. Despite pathologic responses, no objective responses occurred. As per current standards, there is no evidence to support the routine use of neoadjuvant chemotherapy in this setting.
ACKNOWLEDGMENT This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline. Author disclosures and references available online.
OTncologist he
©AlphaMed Press 2015
®
Downloaded from http://theoncologist.alphamedpress.org/ by guest on October 28, 2015
resection. Activity of these agents has been previously documented in STS [2–5], and the use of pazopanib is supported by vascular endothelial growth factor (VEGF)dependent signaling in sarcomas and evidence of antitumor effect in patients with metastatic disease. This was a standard 3 1 3 phase Ib dose escalation. Of the 3 patients treated at dose level 1, 1 experienced dose-limiting toxicity (DLT) (grade 3 fatigue).The cohort was expanded, and 2 additional patients were treated at the same dose level before the trial was discontinued because of slow accrual. Although there were no further DLTs, the combination treatment was poorly tolerated; among 5 patients, 3 discontinued treatment because of toxicity. Although no grade 4 adverse events (AEs) occurred, 4 patients developed grade 3 AEs, which included hypertension, thrombocytopenia, hoarseness, and fatigue (1 patient each), as well as AST/ALT elevations and lymphopenia (2 patients each). There were no objective responses per RECIST; 4 patients had stable disease as best response, and 1 patient progressed. Overall, 4 patients underwent resection of the primary tumor, with significant treatment effect ($90% pathologic response) observed in only 1 patient; 1 additional patient had 70% of pathologic response, and 2 patients had minor responses (#10%). After a median follow-up of 27 months, 3 patients remain disease-free, and 1 patient
Clinical Trial Results
A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas RODRIGO R. MUNHOZ,a SANDRA P. D’ANGELO,a,b MRINAL M. GOUNDER,a,b MARY L. KEOHAN,a,b PING CHI,a,b RICHARD D. CARVAJAL,c SAMUEL SINGER,a,b AIMEE M. CRAGO,a,b JONATHAN LANDA,a,b JOHN H. HEALEY,a,b LI-XUAN QIN,a,b MEERA HAMEED,a,b MARIETTA O. EZEOKE,a ARUN S. SINGH,d MARK AGULNIK,e BARTOSZ CHMIELOWSKI,d JASON J. LUKE,f BRIAN A. VAN TINE,g GARY K. SCHWARTZ,c WILLIAM D. TAP,a,b MARK A. DICKSONa,b a
Memorial Sloan Kettering Cancer Center, New York, New York, USA; bWeill Cornell Medical College, New York, New York, USA; Columbia University Medical Center, New York, New York, USA; dUniversity of California at Los Angeles, Los Angeles, California, USA; e Northwestern University, Chicago, Illinois, USA; fUniversity of Chicago, Chicago, Illinois USA; gWashington University in St. Louis, St. Louis, Missouri, USA Access the full results at: Dickson-15-245.theoncologist.com c
LESSONS LEARNED x Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients.The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib. x Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.
ABSTRACT Background. For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. Methods. Patients with high grade, extremity STS of .8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m2 gemcitabine on days 1 and 8, 75 mg/m2 docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. Results. The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had $90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. Conclusion. GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred. The Oncologist 2015;20:1–2
DISCUSSION The role of systemic therapy in the management of patients with localized STS is a topic of ongoing debate. We sought to investigate whether the addition of pazopanib to gemcitabine/ docetaxel (GDP) in the neoadjuvant setting would be safe and result in an antitumor effect in patients with localized, high grade (limited to undifferentiated pleomorphic sarcoma, high grade leiomyosarcoma, and malignant peripheral nerve sheath tumor), extremity STS of .8 cm amenable to definitive
ClinicalTrials.gov Identifier: NCT01418001 Sponsor: Memorial Sloan Kettering Cancer Center
Principal Investigator: William D. Tap IRB Approved: Yes
Correspondence: Mark A. Dickson, M.D., Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 300 East 66th Street, New York, New York 10065. Telephone: 646-888-4164; E-Mail: [email protected] Received June 16, 2015; accepted for publication August 19, 2015. ©AlphaMed Press; the data published online to support this summary is the property of the authors. http://dx.doi.org/10.1634/ theoncologist.2015-0245
The Oncologist 2015;20:1–2 www.TheOncologist.com
©AlphaMed Press 2015
Downloaded from http://theoncologist.alphamedpress.org/ by guest on October 28, 2015
AUTHOR SUMMARY
Published Ahead of Print on October 8, 2015 as 10.1634/theoncologist.2015-0245.
Neoadjuvant Treatment of Soft Tissue Sarcomas
2
Table 1. Efficacy and treatment summary Best response (change from baseline)
Pt
Histology
Age
Sex
No. of cycles
1
UPS
65
M
2
SD (27.4%)
2
LMS
67
M
3
SD (23.0%)
3 4
UPS UPS
72 42
M F
4 4
SD (21.7%) POD (123.2%)
5
LMS
78
M
2
SD (24.2%)
Pathologic outcomes
AE > grade 2
90% treatment effect; clear surgical margins 10% treatment effect; clear surgical margins Did not undergo surgery 70% treatment effect; clear surgical margins 10% treatment effect; involved surgical margins
Hypertension, fatigue, thrombocytopenia, hoarseness AST/ALT elevation None AST/ALT elevation, lymphopenia Anemia, lymphopenia
Abbreviations: AE, adverse events; AST/ALT, aspartate aminotransferase or alanine aminotransferase; F, female; LMS, leiomyosarcoma; M, male; POD, progression of disease; Pt, patient; SD, stable disease; UPS, undifferentiated pleomorphic sarcoma.
developed lung metastases. Treatment/outcome details are provided in Table 1. Studies investigating neo- or adjuvant systemic treatments in STS have yielded conflicting results. A meta-analysis suggested a marginal improvement in local recurrence, distant recurrence, and overall survival with adjuvant chemotherapy in patient with resectable STS; however, subsequent prospective trials have not confirmed this. In conclusion, the question of whether neoadjuvant chemotherapy can improve the outcomes of patients with localized, high-grade extremity STS remains unanswered. The addition of pazopanib to gemcitabine and docetaxel resulted in significant toxicity. Despite pathologic responses, no objective responses occurred. As per current standards, there is no evidence to support the routine use of neoadjuvant chemotherapy in this setting.
ACKNOWLEDGMENT This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline. Author disclosures and references available online.
OTncologist he
©AlphaMed Press 2015
®
Downloaded from http://theoncologist.alphamedpress.org/ by guest on October 28, 2015
resection. Activity of these agents has been previously documented in STS [2–5], and the use of pazopanib is supported by vascular endothelial growth factor (VEGF)dependent signaling in sarcomas and evidence of antitumor effect in patients with metastatic disease. This was a standard 3 1 3 phase Ib dose escalation. Of the 3 patients treated at dose level 1, 1 experienced dose-limiting toxicity (DLT) (grade 3 fatigue).The cohort was expanded, and 2 additional patients were treated at the same dose level before the trial was discontinued because of slow accrual. Although there were no further DLTs, the combination treatment was poorly tolerated; among 5 patients, 3 discontinued treatment because of toxicity. Although no grade 4 adverse events (AEs) occurred, 4 patients developed grade 3 AEs, which included hypertension, thrombocytopenia, hoarseness, and fatigue (1 patient each), as well as AST/ALT elevations and lymphopenia (2 patients each). There were no objective responses per RECIST; 4 patients had stable disease as best response, and 1 patient progressed. Overall, 4 patients underwent resection of the primary tumor, with significant treatment effect ($90% pathologic response) observed in only 1 patient; 1 additional patient had 70% of pathologic response, and 2 patients had minor responses (#10%). After a median follow-up of 27 months, 3 patients remain disease-free, and 1 patient
